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Lecture I: Genomic Pathology: An Introduction Richard L. Haspel, MD, PhD Mark S. Boguski, MD, PhD 1 TRIG Curriculum: Lecture 1 March 2012
TRIG Curriculum: Lecture 1 1
Lecture I:Genomic Pathology: An Introduction
Richard L. Haspel, MD, PhDMark S. Boguski, MD, PhD
March 2012
TRIG Curriculum: Lecture 1 2
$2,700,000,000
1990-2003
March 2012
TRIG Curriculum: Lecture 1 3
What do I get for $999?
You get access to your raw data of 50 million DNA bases at high quality (80X coverage). You will have access to new tools and content as they are developed, to take full advantage of your exome sequence data. Most excitingly, you'll be a trailblazer, one of the first people on the planet to know their personal exome sequence!
March 2012
TRIG Curriculum: Lecture 1 4
Coming to a clinic near you…
Based on personal experience at Stanford University Hospital & Clinics…patients have already begun to arrive at their physician's office with 23andMe reports in hand seeking expert medical advice.
Salari K. PLoS Medicine. 2009; 6:e1000138
March 2012
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Coming to a clinic near you…
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DefinitionsWhat is a human genome?• A “whole genome” consists of ~3 gigabytes (3 billion “base pairs”) of DNA
distributed unequally among 46 chromosomes (diploid genome).• Approximately 98% of the this DNA is “intergenic” (literally “between genes”),
does not encode proteins and is of unknown medical relevance.What is a humanexome?• Exome refers to the 2% subset of the whole genome that encompasses our
~22,000 pairs of genes.• Because each gene, on average, is composed of 8 protein-encoding
segments (“exons”), an exome corresponds to 8 x 22,000 = 176,000 segments of DNA.
What is a human transcriptome (a.k.a. gene expression profile)?• Transcriptome refers collectively to all of the “expressed” RNA “transcripts”
of genes based on the “central dogma” of molecular biology, i.e. DNA -> RNA -> protein.
• A transcriptome reflects what a cell is doing at a particular point in time (molecular phenotype) as opposed to what it is capable of doing (genotype).
March 2012
TRIG Curriculum: Lecture 1 7
MedicalMicrobiology
Molecular mechanisms of disease
Pharmacogenomics
Medical genetics, preventive medicine
Natural history of disease, response to therapy
Surgical pathology
Kahvejian A,.et al. Nat Biotechnol. 2008; 26:1125-33
Genomic Testing as a Universal Diagnostic
March 2012
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Why Pathologists? We have access, we know testing
PersonalizedRisk Prediction,MedicationDosing,Diagnosis/Prognosis
Physician sendssample toPathology (blood/tissue)
Pathologists
Access to patient’s genome
Genetic CounselorsMedical Geneticists
March 2012
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“[a patient’s genome] is just another lab value.”
-- D.P. DimmockACMG, Vancouver 18 March 2011
Worthey EA, et al. Genetics in Medicine. 2011;13:255
Sample swaps at 23andMe: a cautionary taleBy Daniel MacArthur | June 7, 2010 | 6:00 a.m.
March 2012
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Pathologists in Familiar Role
?*
PathologistsMarch 2012
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Already considering workflow
Roychowdhury S, et al. Sci Transl Med. 2011; 3: 111ra121
March 2012
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What will be the pathology report of the future?
• Ethical issues• Informed consent• Integrated data
interpretationMarch 2012
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Multidisciplinary Teams Needed• Modern medical
technology and practice requires a multidisciplinary approach to medical practice.
• Greater interaction needed between Pathologists, Genetic Counselors and Medical Geneticists
Roychowdhury S, et al. Sci Transl Med. 2011; 3: 111ra121
March 2012
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Training Residents in Genomics (TRIG) Working Group
March 2012
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What we will cover today:• Review present and future
of genomic testing:
– Methods• Single gene• Gene chips• Whole-genome/exome/
transcriptome seqeuncing
– Clinical utility• Prognosis/diagnosis• Risk prediction
– Communicating with the patient
• Single gene• Genomic testing
March 2012
